PROJECT SUMMARY: Dr. Yi-Chen Lai is a board-certified pediatric intensive care physician with a long-standing interest in neuroscience. He completed two years of research training as a T32 fellow at the Children's Hospital of Pittsburgh, and is currently a K12 award recipient at Baylor College of Medicine and is enrolled in the Clinical Scientist Training Program, funded by a K30 grant. He proposes further career development to become a successful, independent investigator in the field of epilepsy. His main research interest is status epilepticus, a prevalent disease of childhood associated with significant mortality and morbidity. During the K12 funding period, Dr. Lai has examined the role of poly(ADP-ribose) polymerase-1 (PARP-1) in status epilepticus. PARP-1 activation was associated with N-methyl-D-aspartate mediated excitotoxicity in many brain pathologies. However, the role of PARP-1 in seizures and status epilepticus remains undefined. He found that PARP-1 was activated during status epilepticus. PARP-1 inhibition decreased neuronal damage in the hippocampus in vivo, and preserved mitochondrial function against oxidative stress ex vivo. He now hypothesizes that PARP-1 is activated in status epilepticus and contributes to several neuropathological changes. He will examine: 1. the temporal, cellular and sub-cellular hippocampal PARP-1 activation in status epilepticus, 2. the effects of PARP-1 activation on the latency of seizures and status epilepticus and hippocampal damage, and 3. the contribution of PARP-1 activation to mitochondrial dysfunction following status epilepticus. This project will solidify Dr. Lai's research background in epilepsy and expand his skills to mitochondrial biology. His mentors, Dr. Anne E. Anderson (epilepsy) and Dr. William J. Craigen (mitochondrial biology) are well-established investigators in their respective fields, each with an excellent record in mentoring young faculty members. Dr. Lai is working in the Cain Foundation Laboratories, members of which have diverse research interests in clinical and basic neuroscience with a focus on epilepsy and thus provide a rich intellectual environment in which to conduct translational research. RELEVANCE: This proposed project has great clinical relevance as status epilepticus is a prevalent and potentially fatal disorder. Understanding the pathologic processes occurring in status epilepticus will provide insights into its detrimental consequences and possibly suggest novel therapeutic interventions.